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Regioselective Asymmetric Aminohydroxylation Approach to a β-Hydroxyphenylalanine Derivative for the Synthesis of Ustiloxin D Haengsoon Park, Bin Cao, and Madeleine M. Joullie´* Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323
[email protected] Received May 11, 2001
β-Hydroxy-R-amino acids are often found as key motifs in biologically active natural products. For example, β-hydroxytyrosine and β-hydroxyphenylalanine residues are structural subunits of many important macrocyclic peptide antibiotics such as vancomycin,1 bouvardin,2 orienticins,3 and phomopsins.4 These amino acids are also useful building blocks for the synthesis of β-lactams.5 As part of our synthetic studies toward ustiloxin D6a (1d, Figure 1), an efficient method was sought for the asymmetric synthesis of a β-hydroxyphenylalanine derivative (2, Scheme 1) as a key intermediate. Ustiloxins,6 whose structures are closely related to those of phomopsins, were isolated from the water extracts of false smut balls caused on the panicles of the rice plant by a fungus, Ustilaginoidea virens. They are potent inhibitors of microtubule assembly and anticancer drug leads.6d,f A literature survey revealed that several strategies have been devised for the asymmetric syntheses of β-hydroxy-R-amino acids: the alkylation of chiral enolates from oxazolidinones, bis-lactims, oxazolines, oxazolidines, and imidazolidinones; the cycloaddition of chiral azomethine ylids; enzymatic transformations; and syntheses via catalytic asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aldol reactions.7 Since most of these synthetic routes involve a multistep * To whom correspondence should be addressed. E-mail: mjoullie@ sas.upenn.edu. (1) (a) Williams, D. H. Acc. Chem. Res. 1984, 17, 364 and references therein. (b) Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915 and references therein. (2) Jolad, S. D.; Hoffmann, J. J.; Torrance, S. J.; Wiedhopf, R. M.; Cole, J. R.; Arora, S. K.; Bates, R. B.; Gargiulo, R. D.; Kriek, G. R. J. Am. Chem. Soc. 1977, 99, 8040. (3) Tsuji, N.; Kobayashi, M.; Kamigauchi, T.; Yoshimura, Y.; Terui, Y. J. Antibiot. 1988, 41, 819. (4) (a) Mackay, M. F.; Donkelaar, A. V.; Culvenor, C. C. J. J. Chem. Soc., Chem. Commun. 1986, 1219. (b) Lacey, E.; Edgar, J. A.; Culvenor, C. C. J. Biochem. Pharmacol. 1987, 36, 2133. (c) Li, Y.; Kobayashi, H.; Tokiwa, Y.; Hashimoto, Y.; Iwasaki, S. Biochem. Pharmacol. 1992, 43, 219. (5) (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49. (b) Labia, R.; Morin, C. J. Antibiot. 1984, 37, 1103. (c) Floyd, D. M.; Fritz, A. W.; Pluscec, J.; Weaver, E. R.; Cimarusti, C. M. J. Org. Chem. 1982, 47, 5160. (6) (a) Koiso, Y.; Lin, Y.; Iwasaki, S.; Hanaoka, K.; Kobayashi, T.; Sonoda, R.; Fujita, Y.; Yaegashi, H.; Sato, Z. J. Antibiot. 1994, 47, 765. (b) Koiso, Y.; Natori, M.; Iwasaki, S.; Sato, S.; Sonoda, R.; Fujita, Y.; Yaegashi, H.; Sato, Z. Tetrahedron Lett. 1992, 33, 4157. (c) Koiso, Y.; Morisaki, N.; Yamashita, Y.; Mitsui, Y.; Shirai, R.; Hashimato, Y.; Iwasaki, S. J. Antibiot. 1998, 51, 418. (d) Li, Y.; Koiso, Y.; Kobayashi, T.; Hashimoto, Y.; Iwasaki, S. Biochem. Pharmacol. 1995, 49, 1367. (e) Iwasaki, S. Med. Res. Rev. 1993, 13, 183. (f) Luduena, R. F.; Roach, M. C.; Prasad, V.; Banerjee, M.; Koiso, Y.; Li, Y.; Iwasaki, S. Biochem. Pharmacol. 1994, 47, 1593. (g) Morisaki, N.; Mitsui, Y.; Yamashita, Y.; Koiso, Y.; Shirai, R.; Hashimoto, Y.; Iwasaki, S. J. Antibiot. 1998, 51, 423. (h) Hamel, E. Med. Res. Rev. 1996, 16, 207.
Figure 1. Structures of ustiloxins.
Scheme 1
preparation of each corresponding chiral auxiliary, intermediate, or a chiral catalyst system, rapid and efficient methods for the synthesis of these important building blocks are still desired. For the synthesis of β-hydroxyphenylalanine derivative 2, we investigated the Sharpless asymmetric aminohydroxylation8 (AA) which could install the requisite stereochemistry of the vicinal amino alcohol function of 2 in a single step. Sharpless and co-workers recently discovered that the use of the AQN ligand (7) For examples, see: (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757. (b) Schollkopf, U.; Beulshausen, T. Liebigs Ann. Chem. 1989, 223. (c) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1983, 24, 3311. (d) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 24, 2545. (e) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chim. Acta 1987, 70, 237. (f) Alker D.; Hamblett, G.; Harwood, L. M.; Robertson, S. M.; Watkin, D. J.; Williams, C. E. Tetrahedron 1998, 54, 6089. (g) Vassilev, V. P.; Uchiyama, T.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 4081. (h) Jung, M. E.; Jung, Y. H. Tetrahedron Lett. 1989, 30, 6637. (i) Shao, H.; Goodman, M. J. Org. Chem. 1996, 61, 2582. (j) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 2507. (k) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (l) Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48. 1999.
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system in the osmium-catalyzed AA reaction of cinnamates reversed the regiochemical outcomes of the previously known PHAL ligand system, affording the N-protected β-hydroxy-R-amino regioisomer as the major product (eq 1).7j Yet, the regioselectivities were moderate, ranging from 4:1 to 3:1, and did not reach to the levels which can be produced for the corresponding R-hydroxy-β-amino regioisomers by the PHAL ligand. Electron-deficient cinnamates were also found to be problematic substrates with the AQN ligand; the AA of m-nitrocinnamate afforded a 1:1 mixture of two regioisomers (enantioselectivities not reported) and a substantial quantity of the diol byproduct. Panek and co-workers, using the same ligand, found that p-aryl esters substituted with strong electron-withdrawing groups (e.g., p-NO2) precluded the aminohydroxylation process.9 On the other hand, in the AA of cinnamates, the PHAL ligand system appeared less affected by the electronic properties of the substrates. This ligand preferentially delivered the nitrogen to the β position with good regioselectivity and enantioselectivity to afford nitro-substituted R-hydroxy-β-amino derivatives. 8b,10,11
Notes Table 1. AA Reactions Using TeocNH2
entry
cat/liga (mol %)
solvent 50% aq
selectivityb 6a:6b
% yieldc 6a, 6b
% eed 6a, 6b
1 2 3
4/5 8/9 4/5
n-PrOH n-PrOH CH3CN
7:3 7:3 1:1
45, 21 37, 17 26, 27
57, 68 67, 75 71, 92
a Catalyst ) K OsO (OH) , Ligand ) (DHQD) AQN. b Ratio of 2 2 4 2 6a to 6b determined by 1H NMR (500 MHz) integration prior to c separation. Isolated yield of 6a and 6b after separation by column chromatography. d Enantiomeric excesses of 6a and 6b determined by HPLC analysis using a Chiralpak AD column with n-hexane/ i-PrOH as the eluent.
using benzyl carbamate and the (DHQD)2AQN ligand (eq 2). The reaction provided a mixture of two regioisomers (5a and 5b, ca. 1:1) in 44% combined yield and significant amounts of the diol byproduct (∼8%). The enantioselectivity obtained for the desired product 5a was only 25%. To improve this result, other nitrogen sources were screened. The reported 2-trimethylsilylethyl carbamate (TeocNH2)10 seemed to be the reagent of choice for this substrate.
In general, the selectivities of asymmetric catalytic reactions are highly substrate dependent. Herein, we wish to extend the scope of the Sharpless AA reaction to electron-deficient olefinic substrates using the AQN ligand for the synthesis of β-hydroxy-R-amino acid derivatives. This method may prove useful for the asymmetric syntheses of nitro- and/or fluoro-substituted aromatic amino acid building blocks12,13 as well as other amino acids14 employed in organic synthesis. Initial tests for the AA reactions were carried out with p-nitrocinnamate 4 under standard carbamate conditions7j (8) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. (c) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 1483. (d) Kolb, H. C.; Sharpless, K. B. Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, pp 243-260. (e) O′Brian, P. Angew. Chem., Int. Ed. Engl. 1999, 38, 326. (9) Morgan, A. D.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1, 1949. (10) Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 3667. (11) Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2821. (12) For nucleophilic aromatic substitution, see: (a) Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem., Int. Ed. Engl. 1996, 35, 1077. (b) Rao, R. A. V.; Gurjar, M. K.; Reddy, L.; Rao, A. S. Chem. Rev. 1995, 95, 2135. (c) Zhu, J.; Laı¨b, T.; Chastanet, J.; Beugelmans, R. Angew. Chem., Int. Ed. Engl. 1996, 35, 2517. (d) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63, 9594. (e) Raeppel, S.; Raeppel, F.; Suffert, J. Synlett 1998, 794. (13) Soloshonok, V. A.; Kacharov, A. D.; Hayashi, T. Tetrahedron 1996, 52, 245. (14) Easton, C. J.; Hutton, C. A.; Roselt, P. D.; Tiekink, E. R. T. Tetrahedron 1994, 50, 7327.
The regioselectivities and enantioselectivities of the aminohydroxylation reactions using TeocNH2 varied with reaction conditions (Table 1). The AA reaction with 4 mol % of the catalyst proceeded with a shorter reaction time of 1.5 h and a regioselectivity of 7:3 for 6a and 6b, affording a 45% isolated yield of the desired isomer 6a in 57% ee (entry 1 of Table 1). Doubling the amount of the osmium catalyst and the AQN ligand slightly enhanced the enantioselectivities of 6a and 6b to 67 and 75%, respectively (entry 2 of Table 1). On the other hand, using CH3CN/H2O (1:1) as the solvent also led to a slight improvement in the enantioselectivity but diminished the regioselectivity to 1:1 (entry 3 of Table 1). Cinnamate 4 was unreactive to the aminohydroxylation at 0 °C. In all three cases, the formation of a small amount of dihydroxylated byproduct (
